The study of anti-HIV nucleosides bearing a conventional deoxyribose backbone continues. The rationale used involves maintaining the critical 3-OH group present in conventional deoxynucleoside substrates (required for chain extension), but adding a 4-alkyl group (methyl and ethyl) to interfere with the chain elongation step. Synthesis of the thymidine series bearing 4-methyl and 4-ethyl groups was successfully completed and the results recently published (J. Mol. Biol. 2007, 371, 873-882). The 4-methyl analogue showed excellent properties as a delayed chain terminator when used in vitro against HIV-RT as a 5-triphosphate, but failed to be recognized by cellular kinases. The recent synthesis of the corresponding 4-methyl deoxyadenosine series, on the other hand, provided a compound that is both successfully phosphorylated by cellular kinases and extremely potent against HIV in infected cells. This represents the first successful design of a compound in this class capable of being activated by cellular kinases and able to function as an effective delay (kinetic delay) chain terminator of viral DNA synthesis, The synthesis of conformationally locked and flat bicyclo[3.1.0]hex-3-ene nucleosides in the south hemisphere of the pseudorotational cycle containing thymine, cytosine, guanine, and adenine as nucleobases was completed. None of the compounds were active against HIV in cell culture. This year we also completed the synthesis of an adenine bicyclo[3.1.0]hexane nucleoside bearing a phosphonomethyl group to bypass the need of phosphorylation by cellular kinases. The template mimics a threose backbone. Biological studies will be performed.